ABSTRACT
The hypercholinergic activity in the brain stimulates the excitotoxic glutamatergic pathways, resulting in seizures that, if persistent and recurring, lead to permanent brain damage. The use of brain-penetrating acetylcholinesterase (AChE) reactivators has the potential of reducing or preventing the seizures and reducing or preventing the brain damage. An interesting rationale underlies the invention of zwitterionic AChE reactivators from the Taylor laboratories. The goal of developing brain-penetrating reactivators is to relieve some of the brain-mediated acute effects of organophosphate (OP) poisoning and ultimately, attenuate or prevent the neuropathology and long-term brain damage of severe OP poisoning. Monoisonitrosoacetone is a small tertiary oxime that would be expected to enter the brain. Oximes conjugated to glucose were synthesized with the premise that they would be recognized by the brain’s facilitative glucose transporter and imported into the brain by this mechanism. These sugar-oximes were reactivators of mouse AChE inhibited by tetraethylpyrophosphate (TEPP) and provided some protection of mice from acute toxicity of TEPP.
